This invention relates to the use of N,N-dimethylglycine (DMG) in combination with at least one component derived from Perna canaliculus to modulate immune responses and to treat inflammatory diseases in man or animals.
N′N-dimethylglycine (DMG), which is a tertiary amino acid, is an intermediary metabolite found in low levels in many foods. It is produced in the body from choline and has been used as a non-fuel nutrient. The physiological and potential therapeutic effects of N,N-dimethylglycine have been evaluated in recent years. References in the literature pertaining to N,N-dimethylglycine and its potential uses include the following: Graber et al., 1981, J. of Infectious Diseases 143:101–105 (DMG stimulation of both humoral and cellular immunity); Kendall and Graber, U.S. Pat. No. 4,385,068 (discusses DMG alleviation of the effects of excess radiation on the immune system); the 1980 Pacific Slope Biochemical Conference, a paper entitled “Decrease of Lactic Acid Concentration in Blood of Animals Given N,N-Dimethylglycine”; March, 1982 issue of Equine Practice, an article entitled “Effect of a Nutritional Supplement Containing N,N-Dimethylglycine (DMG) on the Racing Standardbred” (DMG increased oxygen utilization and thereby decreased lactic acid levels in animals under extreme stress); November-December, 1982 issue of Canine Practice, an article entitled “A Clinical Evaluation of N,N-Dimethylglycine (DMG) and Diisopropylammonium Dichloroacetate (DIPA) on the Performance of Racing Greyhounds”; February, 1987 issue of Let's Live magazine, an article entitled “Dimethylglycine Update, New Studies Confirm DMG Improves Health” (DMG as an immunomodulating agent); February, 1987 issue of Health Consciousness, an article entitled “N,N-Dimethylglycine and the Immune Response” (DMG as an immunomodulating agent); 1987 ASM Annual Meeting, a paper entitled “The Effect of DMG on the Immune Response of Rabbits” (DMG as an immunomodulating agent); Jun. 27, 1987 issue of The Blood Horse, an article entitled “DMG, Properties and Proprieties” (in humans, DMG stimulated B-cells to produce much higher antibody responses, and DMG enhanced the activity of T cells and macrophages); Kendall et al., U.S. Pat. No. 4,994,492 (treatment of melanoma using DMG); Kendall and Lawson, U.S. Pat. No. 5,026,728 (treatment of arthritis and inflammation using DMG); Kendall and Lawson, U.S. Pat. No. 5,118,618 (use of DMG to enhance antibody production).
The use of preparations made from Perna canaliculus for therapeutic effect extends back at least twenty-five years since the mid-seventies. The nutritional and therapeutic properties of freeze-dried Perna canaliculus in alleviating the symptoms of arthritis were reported in Croft, 1979, Relief From Arthritis (Thorsons Publishing Group, Rochester, Vt.). Studies in both animal and human experiments have given mixed results, but indicate overall that certain components in the mussels were potentially helpful in relieving inflammation and pain associated with arthritis. Certain of these studies are as follows: McFarlane, June 1975, New Zealand Medical Journal, pg. 569 (the results of a study of the effects of a Perna canaliculus product called “Seatone” on a small group of arthritic individuals were reported); Rainsford and Whitehouse, 1980, Arzeim-Forsch, pg. 2128–2131 (a freeze-dried powdered preparation of whole mussel which ws given orally to rats showed some modest anti-inflammatory activity in an induced rheumatoid arthritis model); Miller and Ormrod, 1980, The New Zealand Medical Journal 92:187 (a crude fraction of Perna canaliculus had a marked anti-inflammatory effect when administered by intra peritoneal injection in rats); Couch et al., 1982, The New Zealand Medical Journal 95:803 (a protein containing fraction of Perna canaliculus had an anti-inflammatory effect); Caughey et al., 1983, European Journal of Rheumatology and Inflammation 6:197 (in a human study involving forty-seven rheumatoid arthritic patients, no improvement was observed in patients given mussel extract as compared to patients taking the anti-inflammatory drug naproxen); Gibson et al., 1980, Practitioner 224:955 (93:111 (in human trials for both osteoarthritis and rheumatoid arthritis, significant benefits were achieved after three months on a Perna canaliculus preparation, including reduced pain and stiffness and improvement on functional tests); Audeval and Bouchart, 1986, Gazette Medicale 93:111 (in human trials for osteoarthritis, forty percent of subjects showed significant improvement after treatment with a Perna canaliculus preparation); Miller et al., 1993, Agents Actions 38:139 (an aqueous fraction of Perna canaliculus inhibited experimentally induced inflammation in rats); Whitehouse et al., 1997, Inflammopharmacology (a lipid extract of Perna canaliculus exhibited a dose related anti-inflammatory activity).